tbuckley/cabot-search huggingface dataset:
Identification of a novel squalene epoxidase function in breast cancer brain metastasis.
Authors: Shu-Ping Wang, Jia-Yun Yeh, Pony Yu-Ling Lee, Kun-Yuan Lin, Chao Di Chang, Chih-Chieh Yang, Shan-Yun Cheng, Ya Wen Hung, Yung-Lung Yu
Journal: Journal of Clinical Oncology (2023)

e13101 Background: Brain metastases are serious complications of breast cancer and there is no effective treatment. The major therapeutic issues can be attributed to the unique brain microenvironment as well as the difficulty of drug delivery to the brain due to the blood-brain barrier (BBB). BBB limits access of nutrients from the circulation and thereby makes the brain in a special condition that is hypoxic and composed of depleted metabolites, growth factors, and proteins. Nevertheless, tumor cells that are able to metastasize to the brain can necessitate metabolic adaptations for their nutrient availability and thereby succeed to colonize in the brain. However, it is still poorly understood how breast cancer cells alter their metabolic systems to manipulate brain metastasis by overcoming nutritional limitations. Methods: To probe the molecular mechanism of breast cancer to brain metastasis, we compared gene signatures in primary breast tumors and breast-to-brain metastatic tumors, and identified that SQLE (encodes squalene epoxidase, the second rate-limiting enzyme in the cholesterol biosynthesis) could be a leading-edge gene in breast-to-brain metastasis. Using the brain metastatic MDA-MB-231-BR (231-BR) and its parental MDA-MB-231 (231) cell line expressing SQLE shRNAs, we evaluated the effects of SQLE loss on cancer cell migration, invasion, and stemness by wound-healing, transwell invasion/migration, and tumorsphere formation assays. The in vitro cell-based BBB model and in vivo mouse models that develop 231-BR brain metastases were established to verify our hypothesis. Results: While loss of SQLE greatly attenuated cell invasiveness and stemness in both 231 and 231-BR cells, loss of SQLE could only affect the cell migration activity on 231 cells but not 231-BR cells. Since the ability to invade, migrate, and penetrate is critical for invasion of cancer cells, our results strongly imply the novel function of SQLE in breast cancer cell invasion, penetration, and colonization in the brain. Our RNA-seq data further identified a subset of SQLE-affected genes that is uniquely enriched in 231-BR cells and favors brain extravasation and colonization. The in vitro cell-based BBB model and in vivo mouse models that develop 231-BR brain extravasation and colonization finally verified our hypothesis that SQLE may play a unique function to promote breast cancer metastasis into the brain. Conclusions: Our findings provide new insights into contributions by SQLE in breast-to-brain extravasation and colonization and indicate that targeting SQLE may represent a therapeutic opportunity for breast cancer brain metastases.
Clinical and biological heterogeneity in triple-negative breast cancer and HER2-low.
Authors: Xi'e Hu, Ping Yang, Songhao Chen, Gang Wei, Lijuan Yuan, Zhenyu Yang, Lin Yang, Shujia Peng, Yanming Dong, Xianli He, Guoqiang Bao
Journal: Journal of Clinical Oncology (2023)

e12565 Background: HER2-low could be found in some patients with triple-negative breast cancer (TNBC). However, its potential impacts on clinical features and tumor biological characteristics in TNBC remain unclear. Methods: We enrolled 251 consecutive TNBC patients retrospectively, including 157 HER2-low (HER2 low ) and 94 HER2-negtive (HER2 neg ) patients to investigate the clinical and prognostic features. Then, we performed single-cell RNA sequencing (scRNA-seq) with another seven TNBC samples (HER2 neg vs. HER2 low , 4 vs. 3) prospectively to further explore the differences of tumor biological properties between the two TNBC phenotypes. The underlying molecular distinctions were also explored and then verified in the additional TNBC samples. Results: Compared with HER2 neg TNBC, HER2 low TNBC patients exhibited malignant clinical features with larger tumor size ( P = 0.04), more lymph nodes involvement ( P = 0.02), higher histological grade of lesions ( P &lt; 0.001), higher Ki67 status ( P &lt; 0.01), and a worse prognosis ( P &lt; 0.001; HR [CI 95%] = 3.44 [2.10-5.62]). Cox proportional hazards analysis showed that neoadjuvant systemic therapy, lymph nodes involvement and Ki67 levels were prognostic factors in HER2 low TNBC but not in HER2 neg TNBC patients. scRNA-seq revealed that HER2 low TNBC which showed more metabolically active and aggressive hallmarks, while HER2 neg TNBC exhibited signatures more involved in immune activities with higher expressions of immunoglobulin-related genes ( IGHG1, IGHG4, IGKC, IGLC2); this was further confirmed by immunofluorescence in clinical TNBC samples. Furthermore, HER2 low and HER2 neg TNBC exhibited distinct tumor evolutionary characteristics. Moreover, HER2 neg TNBC revealed a potentially more active immune microenvironment than HER2 low TNBC, as evidenced by positively active regulation of macrophage polarization, abundant CD8 + effector T cells, enriched diversity of T-cell receptors and higher levels of immunotherapy-targeted markers, which contributed to achieve immunotherapeutic response. Conclusions: This study suggests that HER2 low TNBC patients harbor more malignant clinical behavior and aggressive tumor biological properties than the HER2 neg phenotype. The heterogeneity of HER2 may be a non-negligible factor in the clinical management of TNBC patients. Our data provides new insights into the development of a more refined classification and tailored therapeutic strategies for TNBC patients.
Morphomic phenotyping of oncologic populations.
Authors: Stewart Wang, Nicholas C. Wang
Journal: Journal of Clinical Oncology (2023)

e13572 Background: We have previously identified body and organ composition measures in pre-treatment CT scans that predict post-treatment mortality or disease recurrence in melanoma as well as esophageal, pancreatic, hepatocellular and lung cancers within single institution cohorts in the US. Similar trends can be identified in Asian cohorts although the absolute range of these body composition measures differ substantially from those in the US. We have also identified body and organ composition measures that predict drug tissue distribution and optimal dosing. The qualitative and relative nature of body and organ composition measures to date have limited their utility for precision treatment of oncologic populations. We have therefore refined the precision, granularity and reliability of these measures (morphomics) in oncologic and reference populations. Methods: Analytic Morphomics, our group’s imaging analysis platform, extracts granular, anatomically-indexed body and organ composition measures from medical imaging. This platform has been updated to use artificial intelligence and nested, supervised machine learning algorithms. Our digital morphomics “assays” are 100% reproducible due to our extensive use of deterministic software algorithms and scalable due to our use of efficient ML algorithms and software code. Our ML models have been trained using state-of-the art techniques in 2D and 3D convolutional neural networks (CNNs) for image segmentation, utilizing repeated randomization cross-validation, hold-out sets, and ensemble modeling methods, with large, broadly representable training image sets, and verified by extensive user testing on clinical scans from nearly 200,000 live subjects. Results: We analyzed curated cohorts reflecting the general United States and Taiwanese population (Ns=5,286; 1,459). In addition, we analyzed oncological cohorts reflecting patients with colon (N=95), ovarian (216), pancreatic (156), and esophageal cancers (Ns=333, 344). Validated morphomic measures include bone mineral density (BMD), visceral fat area (VAT, subcutaneous fat area (SAT), skeletal muscle area (SMA), skeletal muscle density (MD) at multiple vertebral levels. When referenced against measures taken from general non-oncologic (trauma) populations to adjust for non-specific changes due to age and gender, these referenced morphomic measures gain predictive power for mortality and cancer recurrence. Conclusions: The unprecedented level of granularity and precision of these raw and referenced morphomic measures shows clinical utility for improved patient selection, drug dosing as well as evaluation of treatment response and toxicity.
Wolf in sheep’s clothing: Effect of primary lung tumor cells equipped with elevated neuron-like properties on brain metastases formation.
Authors: Fei Xu, Haiyan Xu, Jianming Ying, Yan Wang
Journal: Journal of Clinical Oncology (2023)

e14009 Background: It is clinically significant to decipher the mechanisms underlying lung cancer-associated brain metastases. However, comparative studies on primary tumors between patients with and without brain metastases failed to unveil such mechanisms. Moreover, the clinical observation that the incidence of brain metastases after resection of the primary tumor was as high in lymph node-negative (non-LNM) patients as in those with lymph node metastases (LNM) challenges our established knowledge that lymph node staging correlates with distant metastases. Here, we hypothesized that tumor cells in non-LNM patients might acquire a unique mechanism to develop brain metastases. Methods: We ran whole-transcriptome sequencing and methylation sequencing on paired primary tumor and brain metastases samples from 15 NSCLC patients. We compared the differentially expressed genes (DEGs) between patients with LNM and non-LNM patients. Results: Pathway enrichment analysis showed that GO and KEGG pathways associated with neuronal transmission and synaptic signaling were upregulated in primary tumors of the non-LNM group vs. that of the LNM group. In contrast, brain metastases revealed an inversed trend of differential expression for these pathways between non-LNM and LNM groups. Exploratory validation at methylation level revealed that high expression of the neuronal transmission-associated gene GABRG3 correlated with hypomethylation of this gene (R=-0.39, p=0. 042), responsive to increased expression of GABRG3 in brain metastases. Brain metastases expressed higher neuronal transmission-related signatures than paired primary tumors. Intriguingly, this upregulation of tumor-neuron interactions was more pronounced in patients with lymph node metastases, suggesting that i) lymph node metastases might aid primary tumor to develop brain metastases by promoting the adaptation of tumor cells to the brain microenvironment, while ii) non-LNM patients already acquired neuron-like traits at primary sites, heralding the potential of brain metastases. Conclusions: The hypothetical mechanism of lymph node-negative lung cancer developing brain metastases might be that these tumor cells acquired properties of brain cells as early as in primary sites, masking themselves as ‘sheep’ to communicate with the host’s brain cells, and eventually unmasked as ‘wolf’: brain metastases. Further functional studies are warranted to validate this hypothesis.
Endpoints reported in phase 3 randomized clinical trials at ASCO 2022.
Authors: Laure-Anne Marie Nicole Teuwen, Joanna Alyse Young, Maria Teresa Bourlon, Eva Segelov, Hans Prenen
Journal: Journal of Clinical Oncology (2023)

1570 Background: The goal of phase 3 randomized clinical trials (RCTs) is to show clinically meaningful benefit for patients. An analysis of phase 3 RCTs presented at the ASCO 2022 Annual Meeting (ASCO22) was undertaken to assess which endpoints were evaluated. Methods: A systematic analysis was undertaken of ASCO22 abstracts from phase 3 RCTs reporting primary, secondary, interim, updated, and subgroup analyses, as well as trials reporting methodology of currently enrolling studies. Trials that reported posthoc, exploratory, biomarker, and retrospective analyses of RCTs were excluded. Information from ASCO22 materials and clinical trial registration websites was recorded by two independent researchers. Results: In total, 166 RCTs were identified: 93 trials with 50,781 enrolled patients and 73 trials expected to enroll 52,098 patients. More trials reported on patients with locally advanced/metastatic cancer (64.5%) compared to localized cancer (35.5%). Funding source was pharmaceutical or biotechnology company in 62%. Within locally advanced/metastatic trials, overall survival (OS) was a primary endpoint in 40%, while progression-free survival (PFS) was a primary or co-primary endpoint in 45% and 13% respectively. Other primary endpoints included (invasive) disease-free survival ((i)DFS), event free survival (EFS), overall response rate and pathological complete response. In trials that did not include OS as a primary endpoint, OS was a secondary endpoint in 88% (n = 56/64). Within the localized group, trials were subdivided into adjuvant, neo-adjuvant, definitive and other categories. Within the adjuvant trials (n = 27), the most common primary endpoint was (i)DFS (37%), followed by OS (15%). Other primary endpoints included recurrence-free survival, invasive breast cancer free survival, metastasis-free survival, EFS, and PFS. Across all trials, quality of life (QOL) was never reported as a primary endpoint, however it was as a secondary or other outcome in 53% for locally advanced/metastatic trials and 42% for localized trials. When comparing the endpoints reported in the ASCO22 abstract and meeting materials with those listed on the trial registration website, discordance was noted in 14%. Conclusions: Phase 3 RCTs presented at ASCO22 represented participation from over 100,000 patients, however, fewer than half in locally advanced/metastatic cancer and fewer than one quarter in localized disease utilized OS as a primary endpoint. QOL was listed as an endpoint in roughly one half of all trials. Endpoints reported did not match registration data in a significant minority. Debate over which endpoints should be used for cancer RCTs should be informed by this data.
Preliminary analysis of pyrotinib and dalpiciclib-based therapy in HER2-positive advanced breast cancer (ABC).
Authors: Yongsheng Wang, Peng Yuan, Hua Yang, Yanbing Liu, Jian Yue, Yang Yang, Huajun Li, Jinming Yu
Journal: Journal of Clinical Oncology (2023)

e13027 Background: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and HER2 target agents combined with endocrine treatment (ET) has been demonstrated in hormone receptor (HR)-positive and HER2+ ABC, while little was known about the role of CDK4/6i in HR-/HER2+ ABC. In this prospective, multi-center, multi-cohort, phase 2 study (NCT04095390), we assessed the efficacy and safety of pyrotinib (P) and a CDK4/6i, dalpiciclib (D)-based therapy in HER2+ ABC with disparate HR statuses. Methods: HER2+ ABC females with known HR status were eligible if previously treated with trastuzumab (T). No more than one prior systemic regimen in advanced setting was allowed. Cohort A: HR+ pts received P (320 mg QD) and D (125 mg QD, 21 days on and 7 days off) combined with letrozole (2.5 mg QD). Cohort B or C: HR- pts were randomized to receive P and D combined with or without capecitabine (500 mg TID). Pts were treated until progression or unaccepted toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of Jan. 16, 2023, 33 pts were enrolled. We describe pts' distribution and characteristics. 26 pts had at least one efficacy assessment, and 17 (65.4%) achieved confirmed objective responses. ORR was 66.7% (10/15), 80% (4/5), and 50% (3/6) in cohort A, B, and C, respectively. Among the ITT population, the estimated median PFS was 24.9 mo. (24.9 mo., NR, and 20.2 mo. in cohort A, B, and C, respectively). 32 (97.0%) pts experienced treatment-related adverse events (TRAEs). Grade (G) 3-4 TRAEs occurred in 81.8% of pts, and the most frequent (≥ 10%) ones were neutropenia (72.7%), leukopenia (57.6%), diarrhea (21.2%), and mucositis (12.1%). Safety profiles were similar among cohorts, except more G3-4 mucositis, hand-foot syndrome and thrombocytopenia in cohort B. Two in cohort B discontinued due to toxicity (1 rash, and 1 neutropenia). One death was reported after withdrawal and unrelated to the study. Median OS was not reached. Conclusions: Our study shows P and D combined with ET is effective in HR+/HER2+ ABC, providing a chemo-free option to these pts. In HR-/HER2+ ABC, we preliminarily observed that the addition of chemotherapy could improve effectiveness of P and D, but also increase toxicities. Due to the limited sample, the findings need further confirmation. Clinical trial information: NCT04095390 . [Table: see text]
Lactate-induced lactylation circularly regulates glucose metabolism enzymes in breast cancer.
Authors: Jia-lin Xu, Hong-yu Shen, Zhen Zhu, Jinhai Tang
Journal: Journal of Clinical Oncology (2023)

e13092 Background: Breast cancer is the most common malignant tumor in the female population worldwide and has become the disease with the highest cancer-related mortality. Among the molecular subtypes of breast cancer, triple-negative breast cancer accounts for only 15% of primary malignancies, but due to its increasing recurrence, metastasis, and mortality, we need to find new therapeutic targets to address this phenomenon. Analysis from the field of metabolism found that the level of glycolysis in triple-negative breast cancer was significantly higher than that in other cancers. Glycolysis is a common malignant phenotype of cancer, namely the famous Warburg effect. LDHA is the last metabolic enzyme in the glycolytic pathway, and its expression is increased in triple-negative breast cancer. Lactate is the final product of glycolysis, which converts pyruvate to lactate and NADH to NAD+ under the catalysis of LDHA. The acidic tumor microenvironment formed by the accumulation of lactate will not only affect the progression of tumors and the therapeutic effect of anticancer drugs, but also inhibit the function of immune cells. Lactic acid groups can bind to histones and non-histone proteins to produce a new post-translational modification, lactylation. Methods: Breast cancer cells were infected with lentivirus vectors overexpressing or knocking down LDHA, and cell proliferation and cytotoxicity assay, transwell assay and Lactic Acid Content Assay were performed. To further explore the presence of lactylation of LDHA, immunoprecipitation experiments were performed and the modification sites were mutated to examine the enzymatic activity and function of LDHA. Results: In triple negative breast cancer with strong glycolytic metabolic phenotype, altering LDHA level can affect the biological function of breast cancer cells. Secondly, RNA-seq sequencing results showed that LDHA can affect the protein and transcription levels of MEST and CSTA. Finally, the lactylation of histones was also significantly changed after LDHA dysregulated. Reduced levels of LDHA were accompanied by reduced levels of MEST, CSTA, and histone lactylation. In addition, LDHA itself also has lactic acid modification, and mutations in the modification sites can change the enzymatic activity and function of LDHA. Conclusions: The regulatory axis of LDHA-lactate-lactylation has important value and function in the occurrence and development of breast cancer. LDHA regulates the function of some genes by lactate-induced lactylation of histones. In addition, the lactylation of LDHA can alter the enzyme activity, which may be a new therapeutic target for breast cancer.
Performance validation of an artificial intelligence-powered PD-L1 combined positive score analyzer in six cancer types.
Authors: Taebum Lee, Soo Ick Cho, Sangjoon Choi, Sukjun Kim, Wonkyung Jung, Dasom Lee, Seungje Lee, Mohammad Mostafavi, Seonwook Park, Jinhee Lee, Jaewoong Shin, Seokhwi Kim, Kyunghyun Paeng, Chan-Young Ock
Journal: Journal of Clinical Oncology (2023)

e13553 Background: Programmed death-ligand 1 (PD-L1) expression is a predictive marker for immune checkpoint inhibitors (ICI) treatment in various cancer types. The evaluation of PD-L1 expression level by combined positive score (CPS) correlates with immunotherapeutic response in biliary tract, colorectum, liver, pancreas, prostate, and gastric cancers. This study aimed to assess the performance of an artificial intelligence (AI)-powered PD-L1 CPS analyzer on these six cancer types, and to investigate whether the AI assistance could improve concordance among pathologists. Methods: Lunit SCOPE PD-L1 CPS was developed with 1.51 x 10 6 tumor cells and 8.73 x 10 5 immune cells from 2,372 PD-L1 stained whole-slide images (WSI) or tissue microarray cores from various cancer and normal tissues. The algorithm consisted of tissue area segmentation and cell detection AI models. The AI models calculated the CPS by detecting tumor cells over the tumor area and immune cells over the tumor and adjacent area. The model performance was validated on 135 PD-L1 stained WSIs including the six cancer types, which were interpreted by three pathologists. The concordant CPS classification (≥1 or &lt;1) by two or more pathologists was considered as the consensus. Each pathologist revisited to evaluate WSIs with AI assistance (including visualization and scoring) if there was a discrepancy between the pathologist and the AI model. Results: Of 135 WSIs, 122 (90.4%) were classified as the same CPS subgroup by all three pathologists. The CPS ≥1 and &lt;1 subgroup included 67 (49.6%) and 68 (50.4%) cases, respectively. The overall percent agreement (OPA) of the AI model to the consensus of pathologists was 84.4%, ranging from 78.3% (liver) to 91.3% (biliary tract). The AI-assisted re-evaluation by three pathologists was performed in 17, 19, and 22 WSIs, respectively. According to the AI-assisted revision, the unanimous agreement level was increased to 92.6% (125 cases). The OPA of the AI model to the consensus of pathologists was also increased to 91.9%, ranging from 82.6% (liver) to 100.0% (pancreas). Conclusions: This study shows that an AI-powered PD-L1 CPS analyzer can evaluate the CPS in the six cancer types analyzed here at a comparable level to pathologists. AI assistance can improve the concordance of pathologists' CPS interpretation.[Table: see text]